CN111714499B

CN111714499B - Pharmaceutical composition for treating polycystic ovarian syndrome

Info

Publication number: CN111714499B
Application number: CN202010729727.9A
Authority: CN
Inventors: 郝松莉
Original assignee: Heilongjiang University of Chinese Medicine
Current assignee: Heilongjiang University of Chinese Medicine
Priority date: 2020-07-27
Filing date: 2020-07-27
Publication date: 2021-05-11
Anticipated expiration: 2040-07-27
Also published as: CN111714499A

Abstract

The invention discloses a pharmaceutical composition for treating polycystic ovary syndrome, which comprises a pharmaceutical active ingredient and a pharmaceutically acceptable carrier, wherein the pharmaceutical active ingredient is as follows: (a) (1R,2R) -N- (5-methyl-4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -2- [4- (1H-pyrazol-3-yl) benzoyl ] cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof and (b) optionally other pharmaceutically active ingredients for the treatment of polycystic ovary syndrome. The invention also relates to the use of the compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of polycystic ovary syndrome.

Description

Pharmaceutical composition for treating polycystic ovarian syndrome

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a pharmaceutical composition for treating polycystic ovarian syndrome.

Background

Polycystic ovarian syndrome (PCOS, also known as Stein-Leventhal syndrome) is a disease caused by complicated endocrine and metabolic abnormalities of women in the reproductive age, is characterized by persistent anovulation (ovulation dysfunction or loss) and hyperandrogenism (excess production of male hormones in women), and is mainly clinically manifested by symptoms such as thin menstruation, infertility, hirsutism, obesity, acne, bilateral polycystic increase of ovaries, and the like. The disease can be accompanied by endocrine and metabolic abnormalities such as hyperandrogenism, hyperinsulinemia, increase of luteinizing hormone/follicle-stimulating hormone ratio, and disturbance of insulin resistance and metabolic level, wherein the hyperandrogenism is the prominent characteristic of polycystic ovary syndrome, and especially the local hyperandrogenism environment of ovary can be the key point of the polycystic ovary syndrome.

From the aspect of pathogenesis, polycystic ovary syndrome is a metabolic disease with polygenic genetic tendency, and is a common final expression caused by a plurality of etiological factors, but the exact etiological factors can not be completely determined at present, and are generally considered to be related to heredity, adolescent hyperplasia, hyperinsulinemia and insulin resistance, environmental compounds, mental and psychological factors, certain drug pathogenesis factors, and undiscovered pathogenesis factors can also exist.

At present, the treatment means of polycystic ovarian syndrome mainly comprise traditional Chinese medicine, western medicine, combination of traditional Chinese medicine and western medicine and other modes. The traditional Chinese medicine treatment method mostly takes soothing liver, relieving depression, tonifying kidney, replenishing essence and the like as the treatment principle, and utilizes the traditional Chinese medicine compound to improve yin and yang, qi and blood of the organism, regulate menstruation and assist pregnancy. Yang Jianbing and other people adopt an oral self-made traditional Chinese medicine kidney tonifying, emasculation reducing and pregnancy assisting soup (10 g of prepared rhizome of rehmannia, 10g of pulp of dogwood fruit, 20g of dodder, 10g of medlar, 15g of amethyst, 10g of cornu cervi degelatinatum, 10g of bighead atractylodes rhizome, 20g of poria cocos, 10g of rhizoma pinelliae preparata, 20g of salvia miltiorrhiza, 10g of angelica sinensis, 15g of motherwort fruit, 10g of white paeony root, 10g of fructus psoraleae, 10g of fructus aurantii and 6g of roasted grass) to treat polycystic ovarian syndrome and obtain a good effect (Yang Bing, XuPengli and Yafei. the clinical observation of treating ovulation failure of polycystic ovarian syndrome by combining traditional Chinese medicine and Western medicine [ J ]. Liaoning TCM journal 2011, 38 (. Western medicine treatment methods mainly include reduction of androgen levels using ethinylestradiol cyproterone (darin-35), ovulation induction by clomiphene citrate, reduction of glucose tolerance by metformin, and treatment of insulin resistance, among others.

In view of the complexity of the pathogenesis of polycystic ovarian syndrome, there is an unmet need in the art for drugs to treat polycystic ovarian syndrome.

Disclosure of Invention

The invention aims to solve the technical problem of providing a pharmaceutical composition for treating polycystic ovarian syndrome.

The inventor of the present application unexpectedly found through experiments that (1R,2R) -N- (5-methyl-4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -2- [4- (1H-pyrazol-3-yl) benzoyl ] cyclohexanecarboxamide (hereinafter referred to as compound I) described in the following structural formula I has pharmacological activity of treating polycystic ovarian syndrome, and thus can be used for preparing a pharmaceutical composition for treating polycystic ovarian syndrome

To this end, the present invention provides a pharmaceutical composition for treating polycystic ovary syndrome, comprising a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, wherein the pharmaceutically active ingredient is: (a) compound I or a pharmaceutically acceptable salt thereof and (b) optionally other pharmaceutically active ingredients for the treatment of polycystic ovary syndrome.

Compound I was previously disclosed in patent application WO2016/177703A1 by Aslicon (Sweden) Co., Ltd. WO2016/177703A1 relates generally to pyrazole derivatives useful as inhibitors of 5-lipoxygenase activating protein (FLAP). According to the information reported in the patent document, these pyrazole derivatives are highly effective in inhibiting FLAP and thus inhibiting the production of leukotriene, and thus are useful for the treatment and/or prevention of cardiovascular diseases such as arteriosclerosis, coronary artery disease, coronary heart disease, and the like. The chemical name, structural formula, preparation method and corresponding structural confirmation data of compound I are described in example 17. However, this patent document does not mention that the compounds have pharmacological activity for the treatment of polycystic ovarian syndrome, which constitutes an unexpected finding of the present invention.

The term "pharmaceutically acceptable salt" is used in the sense generally known in the art. For example, pharmaceutically acceptable salts can be formed from compound I with pharmaceutically acceptable inorganic or organic acids, including but not limited to hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, carbonate, bicarbonate, acetate, propionate, benzoate, benzenesulfonate, tartrate, citrate, malate, and the like.

The pharmaceutical compositions of the present invention may optionally contain, in addition to compound I or a pharmaceutically acceptable salt thereof, other pharmaceutically active ingredients useful for the treatment of polycystic ovary syndrome. The invention is not particularly limited with respect to the kind of the other pharmaceutically active ingredients for treating polycystic ovary syndrome. In one embodiment, the further pharmaceutically active ingredient for use in the treatment of polycystic ovary syndrome is selected from one or more of oral contraceptives such as ethinylestradiol cyproterone, glucocorticoids such as dexamethasone and prednisone, ovulation-promoting drugs such as clomiphene citrate, insulin sensitising drugs such as metformin, troglitazone, rosiglitazone and the like.

The pharmaceutical composition of the invention also comprises a pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant a carrier suitable for formulation with an active ingredient into a pharmaceutical composition for administration to a subject without causing unacceptable toxicity to the subject. For the preparation of the pharmaceutical composition, any pharmaceutically acceptable carrier commonly used in the art may be employed. For example, to prepare solid dosage forms for oral administration, solid carriers known in the art may be used. Examples of solid carriers are fillers such as lactose, glucose, powdered sugar, microcrystalline cellulose, starch, dextrin, mannitol, etc.; binders such as methylcellulose, hypromellose, carboxymethylcellulose, microcrystalline cellulose, povidone, starch slurry, mucilage, and the like; disintegrants such as croscarmellose sodium, sodium carboxymethyl starch, crospovidone, hydroxypropyl starch, etc.; lubricants such as magnesium stearate, calcium stearate, talc, and the like. In addition, coloring agents, sweetening agents, flavoring agents, preservatives and the like may also be used as long as they are compatible with the active ingredient already used. The pharmaceutical composition of the present invention can be prepared in the form of, for example, tablets, capsules, powders, granules, pills, etc., using the above-mentioned solid carriers.

The pharmaceutical compositions of the present invention may be administered by any suitable route of administration. Preferably, the pharmaceutical composition according to the invention is administered by the oral route. It will be appreciated that the appropriate route of administration will depend upon a variety of factors including, but not limited to, the age, sex, weight, general medical condition of the patient to be treated, the nature and severity of the disease to be treated.

The amount of compound I of the present invention or a pharmaceutically acceptable salt thereof and optionally other pharmaceutically active ingredients for the treatment of polycystic ovary syndrome in the pharmaceutical composition will be an effective amount, which can be readily determined by one skilled in the art by routine experimentation. For example, the pharmaceutical composition may contain 0.1-100mg, preferably 0.5-50mg, more preferably 1-20mg of Compound I or a pharmaceutically acceptable salt thereof. However, higher doses of compound I or a pharmaceutically acceptable salt thereof may also be used where safe and convenient for the patient.

The invention also provides the use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of polycystic ovary syndrome.

In order that the nature of the present invention may be further understood, embodiments of the present invention and the effects thereof will be described below with reference to specific examples. It is to be understood, however, that such description is merely illustrative of the features and advantages of the present invention, and is not intended to limit the scope of the appended claims in any way.

Detailed Description

EXAMPLE 1 tablet composition

The preparation method comprises the following steps: the formula amounts of compound I, microcrystalline cellulose and lactose indicated were mixed well and granulated with 10mg/ml gelatin solution. The wet granules are then sieved and dried, then mixed with starch, talc and magnesium stearate, sieved and compressed into tablets.

EXAMPLE 2 in vivo experiments on the pharmacological Activity of Compound I on polycystic ovary syndrome

The purpose of this experiment was to investigate the pharmacological activity of compound I of the invention on polycystic ovarian syndrome using levonorgestrel in combination with the human chorionic gonadotropin-induced rat polycystic ovarian syndrome in vivo model.

The experimental method of this experiment is as follows:

experimental animals:

healthy female SD rats of 24 days old were used as experimental animals in this experiment. Animals were kept in a clean animal house with room temperature 20-23 deg.C, air humidity 40% -60%, and light/dark switching every 12 hours. Animals can eat and drink water freely.

The experimental method comprises the following steps:

rats were anesthetized with sodium pentobarbital (concentration: 3mg/ml, dose 30mg/kg body weight), an incision was made about 0.5cm in length in the lower abdomen with a scalpel, levonorgestrel silica gel rods (3mm) (each containing 75mg of levonorgestrel) were embedded with a subcutaneous embedding trocar, and then the incision was closed and sterilized. After 3 days, rat neck was injected with Human Chorionic Gonadotropin (HCG) (dose 1.5 IU/tube) 2 times daily for 9 days. The blank control group was sterilized by suturing only the incision on the day of molding without embedding levonorgestrel silica gel stick, and after 3 days, only the same amount of physiological saline was injected without injecting human chorionic gonadotropin.

After the administration of the human chorionic gonadotropin is finished, the modeled rats are randomly divided into a negative control group, a positive control group, a compound I low-dose group, a compound I medium-dose group and a compound I high-dose group, and each group contains 10 rats. Another 10 unmolded rats were used as a blank control group.

The dosing schedule for each experimental group was as follows:

positive control group: 20mg/kg of cyproterone acetate diluted in physiological saline was administered by gavage 1 time a day for 14 days.

Compound I low dose group: 10mg/kg of Compound I diluted in physiological saline was administered by gavage 1 time per day for 14 days.

Dose groups in compound I: compound I diluted in physiological saline at 20mg/kg was administered by gavage 1 time per day for 14 days.

Compound I high dose group: compound I diluted in physiological saline at 40mg/kg was administered by gavage 1 time daily for 14 days.

Negative control and blank control groups: gavage was given a considerable amount of physiological saline 1 time a day for 14 days.

After 14 days of administration, the rats were bled by cutting their necks, the body weights of the rats were measured, and both ovaries were removed by laparotomy and weighed. Blood samples were centrifuged at 2000r/min for 10min, serum was taken and the levels of follicle stimulating hormone, luteinizing hormone, estradiol, testosterone and sex hormone binding globulin were determined by radioimmunoassay.

The results of the experiment are shown in tables 1 and 2.

TABLE 1 weight and ovarian weight of the rats in each group

Group of	Body weight (g)	Ovarian weight (g)
			Blank control group	103.5±6.8	0.012±0.02
Negative control group	127.3±9.9	0.026±0.05
			Positive control group	120.6±5.7	0.019±0.004
Compound I Low dose group	117.9±7.6	0.018±0.03
			Compound I Medium dose group	113.4±8.2	0.016±0.02*
High dose group of Compound I	106.9±4.1*	0.013±0.01*

TABLE 2 serum hormone levels in the groups of rats

Note: results are expressed as mean ± standard deviation, p <0.05 compared to negative control group.

The results show that the compound I can obviously inhibit the weight gain and the ovarian weight gain of rats, reduce the levels of luteinizing hormone, testosterone and estradiol in the serum of the rats, and simultaneously increase the levels of follicle stimulating hormone and sex hormone binding globulin, has certain dose dependence, and has stronger activity than that of a positive control drug cyproterone acetate under the same dose. Without wishing to be bound by theory, the mechanism may be: compound I can reduce the weight and fat accumulation by suppressing the appetite of rats, so that the cholesterol level in blood is reduced, the raw material for synthesizing testosterone is reduced, and the testosterone level in blood serum is reduced; on the other hand, the compound I can regulate the abnormal serum hormone level of the rat with the polycystic ovary syndrome through acting on the hypothalamus-pituitary-ovary axis, correct endocrine disturbance and further play a role in ovulation promotion for the rat. Therefore, compound I may be a new option for clinical treatment of polycystic ovarian syndrome.

Claims

Use of (1R,2R) -N- (5-methyl-4-oxo-4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-3-yl) -2- [4- (1H-pyrazol-3-yl) benzoyl ] cyclohexanecarboxamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of polycystic ovary syndrome.